In January 2020, the Léon Bérard Center (CLB) reported a suspected excess of pediatric cancer cases between 2013 and 2019 among children residing in Lyon to the Auvergne-Rhône-Alpes Regional Health Agency (ARA) and Santé publique France ARA. A joint investigation with the CLB was launched by Santé publique France ARA based on the agency’s methodological guide. Two descriptive epidemiological studies were conducted: one using data from the National Registry of Childhood Cancers (RNCE) and the other using electronic medical records of children treated at the Institute of Pediatric Hematology and Oncology (IHOPe/CLB) in Lyon. The primary objective of these two studies was to determine whether there was an excess incidence of certain pediatric cancers in the 1st and 4th arrondissements of Lyon. These two descriptive epidemiological studies concluded that there is a statistically significant excess incidence of cancers (all cancers combined) among children aged 0 to 14 years residing in the 1st and 4th arrondissements of Lyon compared to the rest of Lyon and Caluire-et-Cuire (between 2010 and 2019 for the study using RNCE data, 2015–2019 for the CLB study). The standardized incidence ratios (SIR) for all sites were 1.66 (95% confidence interval [CI]: 1.05 to 2.49) for the Santé publique France study based on the RNCE and 1.58 (95% CI: 1.10 to 2.10) according to the CLB study. No excess incidence was found for any specific type of pediatric cancer. Over the 2015–2019 period, there was also a slight excess incidence of pediatric cancers in Lyon compared to France (SIR = 1.39; 95% CI: 1.20 to 1.59; CLB study). Analysis of existing environmental data for the study area did not identify any environmental exposures in Lyon’s 1st and 4th arrondissements that differed from those in the rest of the Lyon metropolitan area and that could be associated with pediatric cancers. Air pollution levels are relatively high but not higher than those in the rest of the metropolitan area. Furthermore, cancer types linked to air pollution (particularly leukemias) do not show an excess in the 1st and 4th arrondissements.Subsequently, a descriptive survey was conducted among 10 families who had contacted the CLB to investigate a potential common environmental exposure among the cases that had not been identified previously. This survey was conducted during the first quarter of 2022, in collaboration with oncologists and epidemiologists from the CLB and IHOPe in Lyon. The study did not identify any common exposure factor among the identified cases, nor did it find any location regularly frequented by more than four of the nine responding children. The locations frequented by three or four children were a school complex, a municipal swimming pool, and a public park. Within each of these three frequented locations, the affected children had cancers of different clinical sites. Overall, despite the moderate excess incidence of pediatric cancers across all sites, the absence of excess incidence for any specific type of cancer, the variety of anatomo-clinical forms of pediatric cancers occurring in the expected age groups, the absence of exposure to proven or plausible environmental risk factors common to all or the majority of cases in Lyon’s 1st and 4th arrondissements but not in the rest of the metropolitan area, are all factors pointing toward a probable random fluctuation in the disease. These findings therefore argue against the existence of a spatio-temporal cluster of pediatric cancers identified in Lyon during the 2010–2019 period in the Croix-Rousse area. The investigation was regularly monitored in collaboration with the group of parents affected by this situation and healthcare professionals. A three-phase presentation (to local authorities, healthcare providers, and parents) was conducted to present the results, gather suggestions and questions from stakeholders, and identify avenues for future action. Following these presentations, it was decided to conduct an update of the study on the incidence of pediatric cancers in Lyon three years after the report’s publication.